Cancer cachexia is a syndrome characterized by anorexia, weight loss, premature satiety, asthenia, loss of lean body mass, and multiple organ dysfunction. The majority of patients with cancer whose disease progresses to metastatic disease develop cachexia during their treatment program and the cachexia contributes to their deaths. The frequency of weight loss in cancer patients ranges from 40% for patients with breast cancer, acute myelocytic leukemia, and sarcoma to more than 80% in patients with carcinoma of the pancreas and stomach. About 60% of patients with carcinomas of the lung, colon or prostate have experienced weight loss prior to beginning chemotherapy. Although the relationship between pretreatment malnutrition (weight loss) and adverse outcome is established, no consistent relationship has been demonstrated between the development of cachexia and tumor size, disease stage, and type or duration of the malignancy. Development of cachexia in the cancer patient is not caused simply by increased energy expenditure by the host or by the tumor. The malignant cachexia is partially related to reduced caloric intake.
Cancer cachexia is not simply a local effect of the tumor. Alterations in protein, fat, and carbohyrate metabolism occur commonly. For example, abnormalities in carbohydrate metabolism include increased rates of total glucose turnover, increased hepatic gluconeogenesis, glucose intolerance and elevated glucose levels. Increased lipolysis, increased free fatty acid and glycerol turnover, hyperlipidemia, and reduced lipoprotein lipase activity are frequently noted. The weight loss associated with cancer cachexia is caused not only by a reduction in body fat stores but also by a reduction in total body protein mass, with extensive skeletal muscle wasting. Increased protein turnover and poorly regulated amino acid oxidation may also be important. Presence of host-derived factors produced in response to the cancer have been implicated as causative agents of cachexia, e.g., tumor necrosis factor-α (TNF) or cachectin, interleukin-1 (IL-1), IL-6, gamma-interferon (IFN), and prostaglandins (PGs) (e.g., PGE2).
Anorexia, with progressive depletion of body stores leading to the cachectic state, is observed in 50% of cancer-bearing patients. Different mechanisms proposed to explain the pathogenesis of anorexia include: (i) increased production of cytokines such as TNF and IL-1, and (ii) increased serotoninergic activity within the central nervous system secondary to enhanced availability to the brain of its precursor, tryptophan. Dickerson, J. W. T. et al., 1976, J. Neurochem 27: 1245–1247 have suggested that diets should be selected to keep the ratio of plasma tryptophan to the sum of neutral amino acids constant. Cangiano, C., et al., 1994, Anticancer Res. 14: 1451–1456 has also disclosed that a close relationship between plasma free tryptophan concentration and anorexia in cancer patients supports the serotoninergic system activity in the pathogenesis of cancer anorexia.
Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, and lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant metastatic sites. Clinical data and molecular biologic studies indicate that cancer is a multi-step process that begins with minor preneoplastic changes, which may under certain conditions progress to neoplasia causing metabolic effects such as cachexia.
Tumor cells differ from normal cells in their metabolism of fat in that tumor cells consume short-chain and medium-chain fatty acids poorly. For example, tumor-bearing mice fed a diet rich in medium-chain triglycerides had less weight loss with a marked reduction in tumor size compared with animals fed long-chain triglycerides. Moreover, there have been problems reported with the use of high levels of medium-chain triglycerides and use of structured lipids has been suggested in some total parenteral nutrition formulas. Moreover, these structured lipids do not provide the same benefits if administered enterally. U.S. Pat. Nos. 4,906,664 and 5,081,105 disclose the use of certain structured lipids in the treatment of cancer. Preparations for enteral nourishment including varying ratios of ω-6 to ω-3 (2.1:1–3.0:1) have also been used in oncologic patients. However, these preparations used proportionately larger amounts of ω-6 to ω-3 fatty acids. Furthermore, these preparations did not include additional amounts of branched-chain amino acids and antioxidants as set forth in the present invention. The use of the polyunsaturated fatty acid eicosapentaenoic acid is suggested for the treatment of cachexia by inhibiting lipolytic activity of lipolytic agents in body fluids and the activity of the enzyme guanidino-benzoatase. See Tisdale, M. J., and Beck, A., U.S. Pat. No. 5,457,130, issued Oct. 10, 1995; and Tisdale, et al. Cancer Research 50: 5022–5026 (August 1990). However, the product taught by Tisdale was in a solid dosage form, requiring an already ill patient to swallow 12–16 capsules per day. This method had serious drawbacks, including difficulty in swallowing, belching, and bad odor.
Thus, the prevention and/or treatment of cachexia and anorexia remain a frustrating problem. Both animal and human studies suggest that nutritional support is largely ineffective in repleting lean body mass in the cancer-bearing host. Randomized trials exploring the usefulness of total parenteral nutrition (TPN) support as an adjunct to cytotoxic antineoplastic therapy have demonstrated little improvement in treatment results. See for example Brennan, M. F., and Burt, M. E., 1981, Cancer Treatment Reports 65 (Suppl. 5): 67–68. This, along with a clear demonstration that TPN can stimulate tumor growth in animals suggests the routine use of TPN in cancer treatment is not justified. Kisner, D. L., 1981, Cancer Treatment Reports 65 (Suppl. 5): 1–2.
Long chain fatty acid bio-pathways and physiological actions are discussed in U.S. Pat. No. 5,223,285 to DeMichele, et al., the entirely of which is incorporated herein by reference.
Also of interest is U.S. Pat. No. 5,444,054 to Garleb, et al. and a related U.S. Pat. No. 5,780,451 (allowed application Ser. No. 08/221,349). These documents describe compositions and methods useful in the treatment of ulcerative colitis. Such compositions include a protein source that can be intact or hydrolyzed proteins of high biological value (col. 21); an indigestible oligosaccharide such as fructooligosaccharide; and a lipid blend containing a relatively high proportion of eicosapentaneoic acid, which contributes to a relatively high ω-3 to ω-6 fatty acid ratio.